Torsemide (or torasemide), namely 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulphonyl]-urea or N-[[(1-methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]-3-pyridinesulphonamide, or 3-isopropylcarbamylsulphonamide-4-(3′-methylphenyl)aminopyridine, C16H20N4O3S, m.w. 348.43, CAS Nr. 56211-40-6, described for the first time in example 71 of the West German Patent DE 25 16 025 dating from 1974, is a compound which has well known applicability in the pharmaceutical field, in particular for the manufacture of diuretic agents. Recently, torsemide has also been proposed for the treatment of cerebral edema (U.S. Pat. No. 5,486,530).
Like many molecules of organic nature, also torsemide shows the phenomenon of polymorphism (the existence of various crystalline modifications) in the solid state, which makes the preparation of solid pharmaceutical forms of it particularly problematic. As is well known to experts in the art, polymorphic forms of a compound demonstrate, by means of their different crystalline structure, distinct physico-chemical characteristics (amongst which not only thermodynamic stability, but also the kinetic characteristics), amongst which, purely by means of example, solubility, with obvious respective consequences on the resulting pharmacokinetics. It can thus occur that some polymorphic forms of a given compound are particularly suited to the preparation of specific solid pharmaceutical formulations with defined characteristics, for example bioavailability in patients, whilst other polymorphic forms instead require completely different formulations or are even unusable. Despite the fact that, clearly, every polymorphic form is characterised by its thermodynamic stability which distinguishes it from the others, the synthesis reactions and the purification treatments used in industry in practice always take place under kinetically controlled conditions, frequently favouring the formation, at least partially, of metastable polymorphic forms. For the expert in the art wishing to formulate pharmaceutical compositions with highly reproducible pharmacokinetics, it is therefore critical not only to understand the single polymorphs of a compound but also their formation conditions in the different synthesis reactions and in the various contemplatable purification methods, because certain polymorphs or mixtures of various polymorphs are frequently poorly suited or poorly usable to its ends. Scrupulous study of the conditions of formation of the various polymorphic forms is also necessary with reference to the storage of the raw materials, in that, according to the relative metastability and following unpredictable interactions, transformations between various polymorphs are also possible downstream of the procedures primarily applied to the attainment of the active ingredient in pure form.
Consequently, following the discovery of the polymorphy of torsemide, numerous and great efforts have been invested by various groups of researchers to explore its single polymorphic forms, the usability of these polymorphic forms in the pharmaceutical field and, last but not least, the conditions which lead to the formation of certain polymorphic forms in certain environments.
For example, in the American Patents re-issue 34,672 and re-issue 34,580, which date from 1985, are described a form I and a form II of torsemide characterised amongst others, respectively, by a melting point interval between approx. 159° C. and approx 161.5° C. for form I and a melting point interval of between approx. 157.5° C. and approx. 160° C. for form II. In particular, a method for the attainment of form I of torsemide in pure form, suitable for the production of solid pharmaceutical forms is also described.
Further verifications have been carried out, independently, in 1994, by a group of Japanese researchers which in the context of a “review” appearing in a scientific magazine (“Chemical structure and physico-chemical properties of torasemide”, Kondo et al. Iyakuhin Kenkyu, Vol. 25, No. 9 (1994)) have carried out very deep physico-chemical studies and have acquired very detailed analytical data on samples of torsemide. New methods of synthesis for various forms of torsemide have also been proposed, then characterised in a very complete manner within the scope of this study. The polymorphic form II of torsemide described in this work is obtained from crude torsemide which is dissolved according to well defined proportions (1:16) in water which is then alkalinised with aqueous solutions of sodium hydroxide until reaching a pH of 10. Later, the pH is lowered by the addition of acetic acid until neutralised (pH 7), and the crystals thus obtained are filtered. In addition, it has been found that it is possible to obtain a pure form I of torsemide from this form II by the resuspension of the crystals of form II in a defined quantity of water with subsequent agitation over 20 days at room temperature. With the objective of exploration of the applicability of the various forms of torsemide for the manufacture of pharmaceutical products, the authors of this article have also explored the relative stability of the polymorphic form I and form II obtained according to their method. Whilst form I has been judged sufficiently stable, form II has instead been held to be poorly stable because it is susceptible to humidity, in that it (auto)-transforms into form I in the presence of just water. As a consequence, it has been concluded by Kondo et al. that form II of torsemide obtained and studied by them is not suitable for the preparation of solid pharmaceutical forms.
Over the following years, various groups have then independently identified further polymorphic forms of torsemide, and have studied the characteristics let alone the conditions for their attainment and they have also proposed them validly usable as active ingredients in the preparation of pharmaceutical compositions. Despite all this work, in part also very recently, and despite the notable amount of data recorded and studies completed, the only polymorphic form of torsemide actually used in the pharmaceutical field up to now in the form of solid administrations, is the form I of torsemide, specifically that described in the American Patent Reissue 34,580 and Reissue 34,672.
In fact, up until a short time ago, torsemide was not quoted in any Pharmacopoeia in the world. Torsemide is entered in the US Pharmacopoeia only in the ambit of the edition published in 2001 (USP25) and valid from January 2002 onwards, whilst the only official specification available up to then which provided instructions on the characteristics of torsemide for use as an active ingredient in pharmaceutical preparations was a monograph published during the Pharmacopeial Forum 26, No. 3, then updated ad Pharmacopeial Forum 26, No. 5. It is important to note that in USP 25 and in the preceding monographs, reference is made exclusively to form I of torsemide, but the relative reference standard, was not—and is still not—available in that it is still missing from the official catalogue of the “USP and FCC Reference Standards and USP Authentic Substances”, including the November–December 2001 edition. The availability of the standard does not even appear in the 1st Supplement to the USP which will be official from the 1st Apr. 2002.
From the above, it is clear that 27 years after the discovery of torsemide, and despite the considerable amount of additional polymorphic forms described, the only polymorphic form effectively used in the pharmaceutical field for the preparation of solid formulations is the form I of torsemide as it is described in the American Patent Reissue 34,580 and Reissue 34,672.
On the other hand, it is known however that the solubility of form I is not optimal with respect to that of the other polymorphs, which is reflected amongst others also in the pharmacokinetic characteristics of the respective solid pharmaceutical forms containing form I of torsemide, and therefore the availability of new pharmaceutical forms which contain other polymorphs of torsemide which show greater solubility is highly desirable. The satisfaction of such an objective is the subject of the present invention.